YAP modifies cancer cell sensitivity to EGFR and survivin inhibitors and is negatively regulated by the non-receptor type protein tyrosine phosphatase 14

Oncogene. 2013 Apr 25;32(17):2220-9. doi: 10.1038/onc.2012.231. Epub 2012 Jun 11.

Abstract

The Yes-associated protein (YAP) is a transcriptional factor involved in tissue development and tumorigenesis. Although YAP has been recognized as a key element of the Hippo signaling pathway, the mechanisms that regulate YAP activities remain to be fully characterized. In this study, we demonstrate that the non-receptor type protein tyrosine phosphatase 14 (PTPN14) functions as a negative regulator of YAP. We show that YAP forms a protein complex with PTPN14 through the WW domains of YAP and the PPXY motifs of PTPN14. In addition, PTPN14 inhibits YAP-mediated transcriptional activities. Knockdown of YAP sensitizes cancer cells to various anti-cancer agents, such as cisplatin, the EGFR tyrosine kinase inhibitor erlotinib and the small-molecule antagonist of survivin, S12. YAP-targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cisplatin / pharmacology
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride
  • Gene Knockdown Techniques
  • Genes, Reporter
  • HEK293 Cells
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Luciferases, Renilla / biosynthesis
  • Luciferases, Renilla / genetics
  • Mice
  • NIH 3T3 Cells
  • Peptide Fragments / chemistry
  • Phosphoproteins / chemistry
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Interaction Mapping
  • Protein Tyrosine Phosphatases, Non-Receptor / chemistry
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*
  • Quinazolines / pharmacology*
  • RNA, Small Interfering / genetics
  • Survivin
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Peptide Fragments
  • Phosphoproteins
  • Quinazolines
  • RNA, Small Interfering
  • Survivin
  • Transcription Factors
  • YAP1 protein, human
  • Erlotinib Hydrochloride
  • Luciferases, Renilla
  • TAFAZZIN protein, human
  • ErbB Receptors
  • PTPN14 protein, human
  • Protein Tyrosine Phosphatases, Non-Receptor
  • Cisplatin